INTRODUCTION TO HEART FAILURE © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027b.

INTRODUCTION TOHEART FAILURE

© 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027b

Contents

Heart failure definition

Etiology

Pathophysiology

Clinical manifestations


• ESC 2012: Heart failure (HF) is an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues1

• ACCF/AHA 2013: HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood2

ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Yancy et al. JACC 2013;62:e147–239

Leftatrium

Rightatrium

Rightventricle

Leftventricle

LV=left ventricularMcMurray. N Engl J Med 2010;362:228–38; Francis et al. Ann Intern Med 1984;101:370–7; Krum, Abraham. Lancet 2009;373:941–55

The pathophysiology of chronic HF

HF symptomsdyspnea, edema, fatigue

Remodeling and progressive worsening of LV

function

Morbidity and mortality arrhythmias, pump failure

Hemodynamic alterations, salt and water retention

These changes lead to systemic neurohormonal imbalance

Damage to cardiac myocytes and extracellular matrix leads to changes in the size, shape and function of the heart (remodeling)

and cardiac wall stress

This may lead to fibrosis, apoptosis, hypertension, hypertrophy, cellular and molecular alterations, myotoxicity


Terminology related to left ventricularejection fraction

McMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442

Systoleventricles contracting

Diastoleventricles relaxing

Amount of bloodpumped out ofthe ventricle

Total amount ofblood in

the ventricle

= Ejection fraction (%)

Heart failure definitionHFrEF and HFpEF

HFrEFEF≤35–40%

HFpEF EF>40–50%

HFpEF: heart failure with preserved ejection fractionMcMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442

Diastolic dysfunction

Systolic dysfunction

HFrEF

EF≤35–40%

HFpEF

EF>40–50%

Echocardiography is a useful method for evaluating left ventricular ejection fraction

Heart failure definitionAn abnormality of cardiac structure or function

Acute infarction

Infarct zone thinning and elongation

Fibrous scar Myocyte hypertrophy

Spherical ventricular dilation

Increased interstitial collagen

Konstam MA, et al. J Am Coll Cardiol Img 2011;4:98–108

From myocardial infarction (MI) to HF: Ventricular Remodeling after MI

Contents


Etiology

Pathophysiology


Krum and Gilbert. Lancet 2003;362:147–58; Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Dickstein et al. Eur Heart J 2008;29:2388–442

Etiology

• Coronary heart disease

• Hypertension

• Valvular disease

• Cardiomyopathy

• Idiopathic cardiomyopathy

• Alcoholic cardiomyopathy

• Toxin-related cardiomyopathy e.g. adriamycin

• Post-partum cardiomyopathy

• Hypertrophic obstructive cardiomyopathy

• Tachyarrhythmia-induced cardiomyopathy

• Infiltrative disorders (e.g. amyloidosis)

Most common causes of Heart Failure

• Congenital heart disease

• Pericardial disease

• Hyperkinetic states

• Anemia

• Arterio-venous fistula

• Beriberi

*Others: Including hypertension, diabetes, exposure to cardiotoxic agents, peripartum cardiomyopathy, etc.

Contents


Etiology

Pathophysiology


Different co-morbidities and pathophysiological processes can lead to different types of heart failure

• A range of risk factors and co-morbidities contribute to the development of HF1

AgeSmokingObesity

HypertensionCoronary artery diseaseDiabetesDyslipidemia

Normal LV structure and function LV remodeling

Subclinical LV dysfunction Clinical HF

Years/months

MI

LVhypertrophy

HFrEFHFpEF

Systolicdysfunction

Diastolicdysfunction

Years

‡ Patients with an LV ejection fraction of 35–50% represent a ‘gray area’ and may have primarily mild systolic dysfunction2 HF=heart failure; LV=left ventricular; LVEF=left ventricular ejection fraction;MI=myocardial infarction1. Krum, Gilbert. Lancet 2003;362:14758; Figure reproduced with permission from Krum, Gilbert. Lancet 2003;362:147–58 Copyright © 2003 Elsevier

Patterns of ventricular remodeling are different for HFrEF and HFpEF

LV=left ventricular; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction Adapted from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Figure reproduced with permission from Grossman W, et al. In: Perspectives in Cardiovascular Research; Myocardial Hypertrophyand Failure. Vol 7. Edited by Alpert NR. New York: Raven Press; 1993:1–15. Copyright © 1993 Wolters Kluwer Health

−

Volumeoverload

Increaseddiastolic pressure

Increaseddiastolic wall stress

Series addition of new sarcomeres

Chamberenlargement

Eccentrichypertrophy

HFrEF

−

Increasedsystolic pressure

Increasedsystolic wall stress

Parallel additionof new myofibrils

Wallthickening

Concentrichypertrophy

Pressureoverload

HFpEF

Left ventriclevolume

overload

Left ventriclepressureoverload

Left ventriclenormal

HFrEF – a condition of volume overload

• characterized by eccentric hypertrophy

• results in thinning of the LV walls, decreased systolic function and enlarged LV volume

HFpEF – a condition of pressure overload

• characterized by concentric hypertrophic growth

• results in normal sized LV cavity with thickened walls and preserved systolic function

Cardiac dysfunction triggers the activation of three compensatory neurohormonal systems

Cardiac structure/function abnormality

Activation of compensatory mechanisms to maintain cardiac output and organ perfusion1

Activated in response to reduced cardiac output1

Short-term effects are beneficial in early HF1

Long-term activation exerts unfavourable effects1,3

NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system;SNS=sympathetic nervous system1. Francis et al. Ann Intern Med 1984;101:370–7; 2. Clerico et al. Am J Physiol Heart Circ Physiol 2011;301:H12–H20; 3. Von Lueder et al. Circ Heart Fail 2013;6:594–605 4. Luchner & Schunkert. Cardiovasc Res 2004;63:443–9; 5. Thysgesen et al. Eur Heart J 2012;33:2001–6

Release of NPs in response to cardiac stress2

Opposes the actions of the RAAS2 and SNS4,5

SNS RAAS NP system

The SNS and RAAS are overactivated in heart failure and are responsible for many of the pathophysiological responses that contribute to disease progression

ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous systemLevin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85

RAASAng II AT1R

HF SYMPTOMS& PROGRESSION

EpinephrineNorepinephrine

α1, β1, β2

receptors

SNS

VasoconstrictionBlood pressure

Sympathetic tone

Aldosterone

Hypertrophy

Fibrosis

Sodium and water retention

VasoconstrictionRAAS activity

Vasopressin

Heart rate

Contractility

Secretion of natriuretic peptides results in a number of responses that act to reduce the symptoms and progression of heart failure

NP=natriuretic peptide; NPRs=natriuretic peptide receptorsLevin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30; Brewster et al. Am J Med Sci 2003;326:15–24


Inactivefragments

NP system

Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy

NPRs NPsNeprilysin

RAASAng II AT1R


Inactivefragments

NP system

Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy

NPRs NPsNeprilysin

EpinephrineNorepinephrine

α1, β1, β2

receptors

As heart failure advances, the RAAS and SNS become the predominantly activated neurohormonal systems

ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous systemLevin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30; Brewster et al. Am J Med Sci 2003;326:15–24

SNS

VasoconstrictionBlood pressure

Sympathetic tone

Aldosterone

Hypertrophy

Fibrosis

VasoconstrictionRAAS activity

Vasopressin

Heart rate

Contractility

Aldosterone suppression

Natriuretic peptides have potential for protection of the heart, vessels and kidneys

Enhanced endothelial functionEndothelin inhibition

Vasodilation

Sympatho-inhibitory

LusitropicAttenuation of cardiac remodeling (LVH) and fibrosis

Antiproliferative effect:reverse vascular remodeling

(arterial stiffness)

ANP

BNP

Renin inhibitionImproved renal hemodynamicsIncreased natriuresis and diuresisAttenuation of renal fibrosis

Inhibition of RAAS

ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; LVH=left ventricular hypertrophy; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone systemFigure reproduced with permission from Boerrigter G, Burnett JC Jr. Expert Opin Investig Drugs 2004;13(6):643–52. Copyright © 2004. Informa Healthcare; Rubattu et al. Am J Hypertens 2008;21:733–41

NPs are released in response to cardiac wall stress and act in the brain, adrenal gland, kidney, vasculature and heart

ANP

Inhibition of renin secretion Decrease in SNS outflow

Decrease in BP

Modulation of arterial and cardiopulmonary baroreceptors

ANP interacts with baroreflex controlof the circulation to inhibit the

activity of the SNS2

ANP and BNP inhibit the RAASvia actions in the kidneysand the adrenal glands1

ANP/BNP

Inhibition of aldosterone secretion

Decrease in BP

Natriuretic peptides inhibit the activity of the RAAS and counterbalance the sympathetic nervous system

ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; BP=blood pressure; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system1. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; 2. Rubattu et al. Am J Hypertens 2008;21:733–41

NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system

Summary

• Hypertension and myocardial infarction are major contributors to the development of heart failure

• The RAAS and SNS are activated in response to reduced cardiac output and are responsible for many of the pathophysiological responses that contribute to disease progression in HF

• Secretion of NPs results in a number of physiological responses that act to reduce the symptoms and progression of HF via inhibition of the RAAS and counterbalance SNS activation

• As HF advances, excessive activation of the SNS and the RAAS occurs leading to cardiac stress and overcomes any benefits of NPs, leading to a neurohormonal imbalance

Contents


Etiology

Pathophysiology


Fluid retention

Pumping action of the heart

grows weaker

Swelling of feet, ankles, abdomen and lower back area

Coughing

TirednessShortness of breath

Pulmonary edema

Pleural effusion


• Main symptoms• Breathlessness

• Orthopnea

• Paroxysmal Nocturnal Dyspnea

• Reduced exercise tolerance

• Fatigue

• Ankle swelling

• Main signs• Elevated jugular venous pressure

• Hepato-jugular reflux

• Third heart sound

• Laterally displaced apical impulse

• Cardiac murmur

Symptoms and Signs

McMurray et al. Eur Heart J 2012;33:1787–847

Goldberg et al. Clin Cardiol 2010;33:e73–80

Dyspn

eaEde

ma

Cough

Orthop

nea

Angina

l/che

st p

ainW

eakn

ess

Noctu

rnal

paro

xysm

s

Nause

a/vo

mitin

gFat

igue

Ascite

s

Men

tal o

btun

datio

nW

eight

gain

Palpita

tions

Abdom

inal p

ain

Clinical manifestationsFrequency of signs and symptoms

Signs and symptoms in 4,537 residents of Worcester, Massachusetts, USA, hospitalized for acute HF between 1995 and 2000

Pat

ient

s (%

)

100

80

60

40

20

0

Class I No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations.

Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations.

Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations.

Class IV Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased.

New York Heart Association functional classification based on severity of symptoms and physical activity

McMurray et al. Eur Heart J 2012;33:1787–847


• Clear relationship between severity of symptoms and survival

• Poor relationship between severity of symptoms and ventricular function

• Patients with mild symptoms may still have a relatively high absolute risk of hospitalization and death

Symptomatic severity of heart failure

NYHA: New York Heart AssociationMuntwyler et al. Eur Heart J 2002;23:1861–6

Clinical manifestationsNYHA class is related to prognosis in chronic HF

1.0

0.9

0.8

0.7

Time (months)

0.6

P<0.001

NYHA II

Sur

viva

l pro

bab

ility

acco

rdin

g t

o N

YH

A c

lass

Among 411 outpatients with NYHA class II, III or IV HF, total mortality was 7.1%, 15.0% and 28.0%, respectively during a mean follow-up period of 1.4 years

0 3 6 9 12 15

NYHA IV

NYHA III


• Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality

• With each acute event, myocardial injury may contribute to progressive LV dysfunction

A progressive condition with high mortality

LV: left ventricularGheorghiade et al. Am J Cardiol 2005;96:11G–17G; Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73

Chronic decline

Mortality

Acute episodes

Disease progression

Function& quality

of life (QoL)

Summary

• Heart Failure is an abnormality of cardiac structure or function leading to failure of the heart to deliver sufficient oxygen to metabolizing tissues1

• The most common cause of HF is coronary artery disease2

• The most frequently reported signs and symptoms of HF are dyspnea, edema and cough3

• HF has a complex pathophysiology involving activation of two key neurohormonal systems:4

• Renin–angiotensin–aldosterone system

• Sympathetic nervous system

• Natriuretic peptides counteract the detrimental effects of RAAS and SNS activation5

RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Lam et al. Eur J Heart Fail 2011;13:18–28; 2. Dickstein et al. Eur Heart J 2008;29:2388–442; 3. Goldberg et al. Clin Cardiol 2010;33:e73–80; 4. McMurray et al. Eur Heart J 2012;33:1787–847; 5. Levin et al. N Engl J Med 1998;339;321–8

INTRODUCTION TO HEART FAILURE © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027b.

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Transcript of INTRODUCTION TO HEART FAILURE © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027b.